BCL2 inhibitor ABT-199 and JNK inhibitor SP600125 exhibit synergistic cytotoxicity against imatinib-resistant Ph+ ALL cells

Chisato Inoue, Sayaka Sobue, Yuka Aoyama, Naoki Mizutani, Yoshiyuki Kawamoto, Yuji Nishizawa, Masatoshi Ichihara, Akihiro Abe, Fumihiko Hayakawa, Motoshi Suzuki, Yoshinori Nozawa, Takashi Murate

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Abstract

Imatinib (IMT), a specific tyrosine kinase inhibitor (TKI), has drastically changed the treatment strategy for Ph+ ALL (Philadelphia chromosome-positive acute lymphoblastic leukemia). However, TKI resistance remains a serious problem for patient prognosis. Here, a Ph+ ALL cell line NphA2 and the IMT-resistant subline NphA2/STIR were analyzed to identify a potential novel treatment strategy. We also examined other Ph+ ALL cells, MR87 and its IMT-resistant subline, MR87/STIR. IMT induced apoptosis of NphA2 and MR87 but had no effect on resistant sublines. Increased phosphorylated ERK and BCL2, but not BCL-XL, were observed in NphA2/STIR compared with NphA2. NphA2/STIR but not NphA2 was moderately sensitive to U0126, an ERK inhibitor. Interestingly, SP600125, a JNK inhibitor, was potent in cell growth inhibition and apoptosis induction of both parental and IMT-resistant NphA2 and MR87 cells. Moreover, NphA2 and MR87 and their IMT-resistant sublines were sensitive to ABT-199, a specific BCL2 inhibitor. The combination of SP600125 and ABT-199 synergistically suppressed both parental and IMT-resistant cells, including one with T315I mutation, suggesting that Ph+ ALL exhibits high sensitivity to ABT-199 and SP600125 regardless of TKI resistance. This combination might be a possible therapeutic strategy for Ph+ ALL in the future.

Original languageEnglish
Pages (from-to)69-75
Number of pages7
JournalBiochemistry and Biophysics Reports
Volume15
DOIs
Publication statusPublished - 09-2018

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All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry

Cite this

Inoue, C., Sobue, S., Aoyama, Y., Mizutani, N., Kawamoto, Y., Nishizawa, Y., Ichihara, M., Abe, A., Hayakawa, F., Suzuki, M., Nozawa, Y., & Murate, T. (2018). BCL2 inhibitor ABT-199 and JNK inhibitor SP600125 exhibit synergistic cytotoxicity against imatinib-resistant Ph+ ALL cells. Biochemistry and Biophysics Reports, 15, 69-75. https://doi.org/10.1016/j.bbrep.2018.07.001